Excipients are utilized in pharmaceutical tablet formulation in roles such as lubricants, disintegrants, glidants as well as filler-binders Bolhuis, G. K., Armstrong, N. A., Excipients for direct compaction—An update. Pharmaceutical Development and Technology 11, 111-124 (2006); Jivraj, M., Martini, L. G., Thomson, C. M., An overview of the different excipients useful for the direct compression of tablets. Pharmaceutical Science & Technology Today 3, 58-63 (2000)). As a binder, an excipient facilitates the consolidation of powders into tablets. This is a process of reducing pores in a powder bed while creating interparticulate bonds to prepare a compact solid unit dosage. The structure of the powder sample in a die changes and consolidation is brought about by combined actions such as particle rearrangement, plastic deformation, and fragmentation. Another role of the excipients is to negate poor flow, packing density, and compaction properties of the active pharmaceutical ingredients (APIs). For example, when the API is made of fine particles that are cohesive, the importance of achieving good flow and packing of a blend by the inclusion of an excipient is very important. Unfortunately, because API particles are cohesive, such impact is significant unless the drug loading is relatively low, such as about 10 wt % or more preferably about 5 wt %. If the drug loading is higher than about 10%, direct compaction cannot be employed, and granulation such as dry roller compaction or wet granulation may be necessary.
Fine excipients improve tablet strength due to larger available surface area. During powder compaction, particles undergo rearrangement, fragmentation, elastic and plastic deformation. The mechanical integrity of the powder compact is provided by interparticle bonds, which include solid bridges, intermolecular forces, and mechanical interlocking. As explained by the bonding area and bonding strength (BABS) model (Sun et al., Decoding Powder Tabletability: Roles of Particle Adhesion and Plasticity, Journal of Adhesion Science and Technology, 25:4-5, 483-499 (2011)), the strength of a tablet is the result of the increased bonding area due to densification and bonding strength between particles. From this theoretical perspective, fine excipients are advantageous to increase bonding area. However, fine excipients have poor flow and hence currently available fine excipients do not satisfy all the desired requirements. For example, Avicel 105 has superior compaction properties mainly attributed its large bonding surface area (Leuenberger, H., Application of percolation theory in powder technology. Advanced Powder Technology 10, 323-352 (1999); Shi, L., Sun, C. C., 2011. Overcoming poor tabletability of pharmaceutical crystals by surface modification. Pharmaceutical Research 28, 3248-3255 (2011)). However, its fine particle size (˜20 μm) makes it very cohesive, leading to relatively low bulk density, flowability (Castellanos, A., The relationship between attractive interparticle forces and bulk behaviour in dry and uncharged fine powders. Advances in Physics 54, 263-276 (2005); Chen, Y., Jallo, L., Quintanilla, M. A. S., Dave, R., 2010. Characterization of particle and bulk level cohesion reduction of surface modified fine aluminum powders. Colloids and Surfaces A: Physicochemical and Engineering Aspects 361, 66-80 (2010); Geldart, D., Abdullah, E. C., Verlinden, A., 2009. Characterisation of dry powders. Powder Technology 190, 70-74 (2009); Huang, Z., Scicolone, J. V., Gurumuthy, L., Davé, R. N., Flow and bulk density enhancements of pharmaceutical powders using a conical screen mill: A continuous dry coating device. Chemical Engineering Science 125, 209-224 (2015)). That leads to consequent handling and feeding problems in pharmaceutical industrial processing. Another example is Avicel 200, which has excellent flow properties. However, the large particle size of Avicel 200 (˜200 μm) results in poor compactability relative to Avicel 105 (Rojas, J., Kumar, V., Comparative evaluation of silicified microcrystalline cellulose II as a direct compression vehicle. International Journal of Pharmaceutics 416, 120-128 (2011)).
Various attempts to improved excipients have been made based on the use of MCC along with flow and compaction promoting agents such as silica and surfactants. The processes for preparing the excipients are variations of granulation and/or spray drying, requiring use of additional materials such as liquids, solvents, binder. In addition, the excipients require drying and subsequent processing to produce the required size distributions. See as examples, U.S. Pat. Nos. 6,746,693; 6,858,231; 6,866,867; and 6,936,277. One commercial example of this type of excipient is PROSOLV® SMCC.
The use of flow promoting agents such as silica by itself does not lead to improved compaction properties. Examples are shown where dry blending of the similar ingredients does not lead to improved compaction properties as compared to the same ingredients that undergo wet granulation type processes that create intimate contact between microcrystalline cellulose (MCC) and silica. The addition of silica may reduce the free surface energy of the mixture because, in most cases, silica has lower surface energy than the excipient. However, the presence of silica can lead to inferior compaction properties since lower surface energy leads to weaker tablets. For example, in Fichtner, F., et al., Effect of surface energy on powder compactibility. Pharmaceutical Research 25, 2750-2759 (2008), decrease in tablet strength correlated to the decrease in powder surface energy at constant tablet porosities. Thus, dry processing of an ordinary excipient with silica is not expected to lead to improved tablet compaction properties, even though the flow may be enhanced because of silica.
Dry processing has been shown to be of benefit in enhancing the flow of a variety of powder materials, usually by mixing with glidants, such as fumed or colloidal silica, titania, talc, etc. These “dry blending” techniques and processes have been shown to enhance the flowability of cohesive particles. For example, U.S. Pat. No. 6,833,185 (the '185 patent) describes dry blending of fluidization additives with cohesive powders. The fluidization additives are characterized by a smaller size and lesser mean particle density relative to the cohesive fine powders to which they are added. Of note, “dry blending” in the '185 patent merely blends the fluidization additives with the underlying cohesive powders and does not affect a “coating” of the additives onto (or with respect to) the underlying cohesive powders, as would be the case in “dry coating”. This was made clear in Yang, J., et al., Dry particle coating for improving the flowability of cohesive powders. Powder Technology 158, 21-33 (2005), where flow enhancement of cornstarch was examined as a result of “dry blending” with silica compared to “dry coating” with silica. It was shown that flow enhancements are significantly better after dry coating with the same amount of silica instead of ordinary blending.
Researchers from the New Jersey Institute of Technology (NJIT) have investigated dry coating techniques that are superior to dry blending. For example, dry particle coating concepts and techniques are described by Pfeffer et al. in an article entitled “Synthesis of engineered particulates with tailored properties using dry particle coating,” Powder Technology 117 (2001), pgs. 40-67, the contents of this article are incorporated herein by reference in its entirety. Here, a dry particle coating may be used to create new-generation materials by combining different powders having different physical and chemical properties to form composites. The new-generation materials described by Pfeffer et al. exhibit unique functionalities and/or improved characteristics relative to known materials. Pfeffer et al. describe techniques for mechanically coating materials ranging in size from 1-200 μm with submicron particles in the absence of a liquid (e.g., a solvent, binder or water).
Dry coating is best done using mixing devices that have higher process intensity. Devices known in the literature for dry coating include, the Hybridizer by Nara Machinery, Japan; the Mechanofusion and its newer variations by Hosokawa Micron, Japan; the Magnetically Assisted Impaction Coating by Aveka, Minnesota; and even a V-blender with in intensifier bar. More recent investigations from New Jersey Institute of Technology (NJIT) and others have revealed that a variety of other high intensity mixing devices may be used. For example, a high-intensity vibration unit called LabRAM, and its larger scale versions from Resodyn, Montana, may be used successfully. Likewise, a conical mill, e.g. Quadro Comil models, may be used under certain conditions to achieve dry coating as disclosed in Huang et al, 2015 (referenced above). U.S. Pat. No. 8,252,370 (the '370 patent) discloses another continuous method where simultaneous milling and coating may be accomplished. As will be apparent to those skilled in art, devices that can provide high intensity mixing actions without significant attrition may be used for dry coating. In dry coating, the finer particles, typically called the guest particles, are coated on to coarser particles, typically called the host particles. FIGS. 1a-e of the present application illustrates this concept for nano-silica coated onto cornstarch. Note that FIG. 1a is a typical un-coated, as received cornstarch particle.
Dry coating is gaining significant interest for pharmaceutical applications. It has been shown that dry coating with flow enhancing agents leads to reduced cohesion, improved flow, increased packing density, and even reduced electrostatic tendency. Observed property enhancements are attributed to intimate coating and spreading of the materials such as nano-silica, as discussed in various publications, see for example, Chen, Y., et al., Fluidization of coated group C powders. AIChE Journal 54, 104-121 (2008); Han, X., et al., Simultaneous micronization and surface modification for improvement of flow and dissolution of drug particles. International Journal of Pharmaceutics 415, 185-195 (2011); and Jallo, L. J., et al., Improvement of flow and bulk density of pharmaceutical powders using surface modification. International Journal of Pharmaceutics 423, 213-225 (2012). As an example of dramatic improvements in bulk density and flow, FIGS. 2a-b of the present application illustrates that if there is no silica or dry coating, how packing density decreases and cohesion increases as ibuprofen is micronized down to sizes ranging from about 28 to 5 microns. In contrast, if simultaneous dry coating is done while milling, the decrease in bulk density and increase in cohesion are significantly eliminated. Also, the properties improve drastically as compared to simple silica blending as shown for 5 and 28 micron sized powders. In addition, dry coating with hydrophilic silica has also been shown to greatly reduce electrostatic charging tendency, for example, in Jallo, L. J., et al., “Explaining Electrostatic Charging and Flow of Surface-Modified Acetaminophen Powders as a Function of Relative Humidity Through Surface Energetics”, Journal of Pharmaceutical Sciences, 104, 2225-2232 (2015).
Chen et al. 2008 (referenced above) demonstrates that mechanistic models can predict how the extent of guest particle coverage impacts reduction in particle cohesion forces which lead to reduced cohesion and hence improved flow and packing. Based on the contact model developed by Chen et al. 2008, an important factor called guest particle surface area coverage (SAC) is identified. While the derivation assumes that host and guest particles are monodisperse, the guest particles are uniformly coated on to host particles, and that the amount is only sufficient to create a monolayer, the relationship between the guest wt % and percentage SAC (in range 0 to 100) is given by the Equation (1). Here N is the average number of guest particles per host particle, d is the diameter of the guest, D is the diameter of the host, and □d and □D are material densities of guest and host respectively.
                                              ⁢                              Wt            ⁢                                                  ⁢            %                    =                                                    (                                                      Nd                    2                                    ⁢                                      ρ                    d                                                  )                                                              (                                                            D                      3                                        ⁢                                          ρ                      D                                                        )                                +                                  (                                                            Nd                      3                                        ⁢                                          ρ                      d                                                        )                                                      ×            100            ⁢            %                                              (        1        )                                SAC        =                                                            N                ×                                                      π                    ⁢                                                                                  ⁢                                          d                      2                                                        4                                                            4                ⁢                                                      π                    ⁡                                          (                                                                        d                          +                          D                                                2                                            )                                                        2                                                      ×            100            ⁢            %                    =                                                                      N                  ×                                      d                    2                                                                    4                  ⁢                                                            (                                              d                        +                        D                                            )                                        2                                                              ×              100              ⁢              %                        ≈                                                            N                  ×                                      d                    2                                                                    4                  ⁢                                      D                    2                                                              ×              100              ⁢              %                                                          (        2        )            
In Equation (1), given a desired SAC, given by Equation (2), N and guest wt % can be computed. It is shown through particle contact models that desired SAC is between about 1 and 100%. In addition, these contact models also indicate that the desired size of the silica particle should be in range about 5 nm to 30 nm. In this invention, selection of the best silica considers these and other factors such as its impact on flow and bonding strength. If the coating device is efficient and the host and guest materials have compatibility based on their surface free energy as disclosed in Huang et al. 2015, coating can indeed be very uniform and theoretical SAC predicted from these equations would be fairly close to experimental, as shown in Yang et al. 2005.
Overall, the prior efforts have attempted to disclose various aspects of better compacting excipients that include silica, surfactant and other materials, they have not shown how dry processing can lead to better compacting excipients. Rather, it has been demonstrated that dry blending did not provide improved compaction properties, see for example, Chattoraj, S., et al., Profoundly improving flow properties of a cohesive cellulose powder by surface coating with nano-silica through comilling. Journal of Pharmaceutical Sciences 100, 4943-4952 (2011); Zhou, Q., et al., “Preparation and Characterization of Surface-Engineered Coarse Microcrystalline Cellulose Through Dry Coating with Silica Nanoparticles,” Journal of Pharmaceutical Sciences, 101:4258-4266 (2012). It was shown that dry coating of silica on fine (Avicel® 105), and coarse (Avicel 102) excipients may be achieved using many passes of a conical milling device, e.g., comil. The resulting product was found to have enhanced flow. These dry coated excipients produced weaker 100% MCC placebo tablets, although the tablet strength was found to be still acceptable for Avicel 105 as long as sufficiently high compaction force was used. This work did not show tablet compaction using pharmaceutical blends of API and dry coated excipients. However, it is expected that blending the dry coated excipients with poorly flowing and poorly compacting APIs, tablets would not achieve sufficient compaction. The prior art suggests that dry coating will lead to poorer compaction properties because it is likely to lead to reduced surface energy after dry coating (Sun, C., “Decoding Powder Tabletability: Roles of Particle Adhesion and Plasticity,” Journal of Adhesion Science and Technology, 25:483-499 (2011); Fichtner, et al. 2008; Etzler, F. M., et al., Tablet tensile strength: An adhesion science perspective. Journal of Adhesion Science and Technology 25, 501-519 (2011); and Han, X., et al., Passivation of high-surface-energy sites of milled ibuprofen crystals via dry coating for reduced cohesion and improved flowability. Journal of Pharmaceutical Sciences 102, 2282-2296 (2013)).
For commercially available excipients, one or more properties, e.g., flow, packing density, compaction, hydrophobicity, is sacrificed in order to meet a specific property. For example, finer grades of Avicel, e.g., PH105, have better compaction properties, largely attributed to higher surface area, but its finer size makes it poorly flowing and less dense. For example, PROSOLV® SMCC, hereafter “Prosolv”, a commercially available excipient considered to have good flow, density and compaction properties, contains large amounts (˜2%) of nano-silica. Higher silica content negatively impact flexibility in formulating tablets since total silica amounts must be kept within physiologically acceptable limits. In addition, the manufacturing process such as in Prosolv may have bigger environmental footprint and extra steps in processing.
There is a need for improved excipients that have superior flow properties while, at the same time, producing a pharmaceutical tablet with sufficient strength. There is also a need for excipients that facilitate direct compaction even at relatively large drug loadings, for example, 20 wt %, 30 wt %, or even as high as 50 wt % or higher. Thus, there is a need in the art for an excipient having good flow property, good packing density, and good compactibility. The excipient should have a fine size, e.g., D50 under 50 microns. In some embodiments, a particle size where D90<90 microns is preferred. The excipient should also have a simplified manufacturing scheme and minimal use of silica or other flow promoting agents. The role of an excipient is to allow preparing better blend formulations so that even for fine and cohesive API powders, the blend can be produced having good flow (measured by FFC, for example), good bulk density, and importantly, good binding properties for making tablets while reducing the amount of excipient required. It would be beneficial to have excipients that can be used in lesser amounts so that the drug amount in a tablet, i.e., percent drug loading, can be increased. There is also an important consideration with respect to manufacturing process used to go from a blend to tableting. Most desired route is what is called direct compression or compaction. In that case, the blend is directly converted to a tablet using a high-speed tableting machine. If the blend does not have desirable flow, bulk density and compaction properties, the next option is dry granulation, which is usually done via roller compaction. This processing route adds a few steps to manufacturing process but avoids use of liquids and associated need of drying which is the case for wet granulation. Thus, good excipients may facilitate wider use of direct compression; failing which, roller compaction and thus avoid use of wet granulation. For example, it is suggested by Sun, 2010, and Shi et al., 2011 (Sun, C. C., 2010. Setting the bar for powder flow properties in successful high speed tableting. Powder Technol. 201, 106-108; Shi, L., Chattoraj, S., Sun, C. C., 2011. Reproducibility of flow properties of microcrystalline cellulose—Avicel PH102. Powder Technol. 212, 253-257) that the bulk density and the FFC (at 3 kPa consolidation stress) of Avicel® 102 may be used as benchmark values to assess suitability of a blend for high-speed direct compaction tableting. These values are: bulk density of about 0.325 g/mL and FFC of just under 7. Based on this recommendation a person skilled in art can develop a guideline for blend suitability for direct compression, roller compaction, and wet granulation as: Direct compression possible when FFC>about 7, and BD>about 0.32 g/mL; roller compaction when FFC>about 3, and BD>about 0.27 g/mL; otherwise, wet granulation may be necessary. Though this recommendation can act as a guideline to one of ordinary skill in the art, it does not include binding properties and corresponding tablet mechanical properties.
Since direct compression is the easiest path to tablet manufacturing, excipients need to be developed that facilitate direct compression or compaction of tablets even at relatively large drug loadings, for example, 20 wt %, 30 wt %, or even 50 wt % and higher. The excipients should also facilitate roller compaction when very high drug loading may not allow for direct compression at much higher drug loadings, for example, about 70 wt % or higher. Therefore, excipients with excellent binding properties that enable broader ranges of blend formulations than previously possible are desirable.
Developing formulations at higher drug loadings become more challenging when the API is fine or cohesive. A cohesive API has poor flow and bulk density; typically, FFC is 3 or lower, and bulk density is about 0.2 or lower. A good example of this is micronized acetaminophen (mAPAP) which has D50 of about 10 microns and was a subject of an interesting study by Huang et al., “Improved blend and tablet properties of fine pharmaceutical powders via dry particle coating,” International Journal of Pharmaceutics, Vol. 478(2) p 447-455 (2015). This study considered the API (mAPAP) before and after dry coating, where dry coating using a hydrophobic silica R972P was intended to improve flow (FFC) and bulk density of mAPAP. In this study, mAPAP was considered as a model cohesive API and dry coated mAPAP was considered as not cohesive because the study showed (refer to FIG. 1 in Huang et al., 2015) that as-received mAPAP had FFC of about 2 and bulk density of about 0.2 g/mL; and after dry coating with R972P, FFC increased to about 4 and bulk density nearly doubled.
This study also considered blends of mAPAP and an excipient at 10 wt %, 30 wt %, and 60 wt % drug loading. As was shown in FIG. 3 of Huang et al. 2015, for 10% drug loading with using fine excipients (combination of Avicel 105® and Lactose 450), the difference between FFC and bulk density for mAPAP with and without dry coating was not significant. However, when drug loading was 30% or 60%, the non-dry coated API (mAPAP) had poor flow (FFC of below 3) and those blends cannot be used for direct compression tableting. In contrast, the dry coated API was not cohesive, where the FFC increased considerably and so did bulk density. This study showed that having a better excipient is highly desirable as drug loading increases beyond about 10% for cohesive APIs. The blend (FIG. 3 of Huang et al. 2015) also considered a dry coating excipient including Avicel 105® in combination with a dry coated API, and the results indicate that as drug loading increases, there is only a marginal impact of better flowing excipient. Such results are consistent with our results for well-flowing excipients such as Avicel® 102 and Prosolv® 90 HD, which do not provide good flow for even 30 wt % mAPAP blends (see FIG. 17(b)), and for 60% mAPAP loading, they are very poor in terms of FFC and bulk density of mAPAP blends (see FIG. 17(c)).
As discussed above, FFC and bulk density are necessary conditions for direct compression but are not alone sufficient since binding properties are also important. Huang et al., 2015 showed what happens to tablet strength for cohesive (as-received mAPAP) and not cohesive (dry coated mAPAP) APIs. As shown in FIG. 6 of Huang et al., 2015 compared to placebo tablets, the blend tablets had reduced strength for both fine and coarse set of excipient blends. However, these results indicate that even when the tablet strength is drastically reduced, when the API was dry coated, the tablet strength loss was lesser. It has been shown that the tablet strength becomes lower when surface energy is reduced by Nazik A. El Gindy and Magda W. Samaha, Tensile strength of some pharmaceutical compacts and their relation to surface free energy, International Journal of Pharmaceutics, 13:35-46; Effect of surface energy on powder compactibility, Pharmaceutical Research, Vol. 25, No. 12, 2750-2759 (1983); Frank M. Etzler, et al., Tablet Tensile Strength: An Adhesion Science Perspective, Journal of Adhesion Science and Technology, 25:4-5, 501-519 (2011). This explains why the blends had poorer tablet strength since surface energy of mAPAP is higher than the excipients. For blends, Etzler et al., 2011 propose equations that indicate that the strength of a compact of a mixture is proportional to surface energy of individual constituents, weighted by an exponent that is their individual surface area fractions (see equation 21 of Etzler et al., 2011). Thus, when an excipient is dry coated, which reduces its surface energy, will lead to poorer compact strength. Therefore, based on the studies of Huang et al., 2015, one of ordinary skill in the art would conclude that dry coated excipients would produce blends having sufficient table strength. Moreover, the work of Huang et al. 2015 was to show that dry coating a fine cohesive API eliminates the influence of the excipients (see FIG. 5 of Huang et al. 2015) in terms of blend FFC and bulk density. In terms of their fortuitous results for tablet strength of dry coated mAPAP blends being higher than corresponding blends of as received mAPAP, Changquan Calvin Sun, Decoding Powder Tabletability: Roles of Particle Adhesion and Plasticity, Journal of Adhesion Science and Technology, 25:4-5, 483-499 (2011) offers a partial explanation. Sun 2011 discussed that the bonding area-bonding strength (BABS) model should be considered, which suggests that both the bonding strength, considered related to surface energy, and bonding area have an impact. Sun 2011 stated that; “The BABS model can explain the observations that particle size influences tabletability of plastic powders but not of brittle powders.” Further, “ . . . tabletability of lubricated powders is better than that of unlubricated powders for brittle materials”. Thus, for the API (mAPAP), which is brittle material, compared to the excipient (microcrystalline cellulose (MCC) and Avicel® grades) which are ductile, one of ordinary skill in the art would not expect adverse impact of dry coating APIs based on Huang et al. 2015. In addition, dry coated mAPAP has significantly reduced agglomeration as compared to as-received mAPAP, hence its effective bonding area is higher, which as per BABS model explain why tablet strength for dry coated mAPAP blends is higher than as-received mAPAP. On the other hand, for ductile excipients, dry coating would not be advisable since doing so would lead to poorer tablet strength in a blend since the excipients would have reduced surface energy, hence bonding strength and unlike brittle, more cohesive APIs, corresponding increase in surface area is unlikely to compensate for reduced bonding strength.
There is a need in the art for an excipient having good flow property, good packing density, and good compactibility not just by itself but in blends at higher drug loadings, in particular for cohesive APIs. Excipients like Avicel 102® and grades of Prosolv® have excellent compaction properties by themselves, but are poor in blends of cohesive APIs, even when the API is dry coated.